노윤하 (성균관대학교)

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성균관대학교

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PLoS Med., 2022 Mar 2;19(3):e1003945 | https://doi.org/10.1371/journal.pmed.1003945 First-trimester exposure to benzodiazepines and risk of congenital malformations in offspring: A population-based cohort study in South Korea

Yunha Noh^1☯, Hyesung Lee^1,2☯, Ahhyung Choi¹, Jun Soo Kwon^3,4,5, SeungAh Choe⁶, Jungmi Chae⁷, Dong-Sook Kim^7*, Ju-Young Shin^1,2,8*

¹School of Pharmacy, Sungkyunkwan University, Suwon, South Korea, ²Department of Biohealth Regulatory Science, Sungkyunkwan University, Suwon, South Korea, ³Department of Psychiatry Seoul National University College of Medicine, South Korea, ⁴Department of Brain and Cognitive Sciences, Seoul National University College of Natural Sciences, South Korea, ⁵Institute of Human Behavioral Medicine, Seoul National University Medical Research Center, South Korea, ⁶Division of Life Sciences, Korea University, Seoul, South Korea, ⁷Department of Research, Health Insurance Review and Assessment Service, Wonju, South Korea, ⁸Department of Clinical Research Design & Evaluation, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, South Korea

^☯ These authors contributed equally to this work.

^*Corresponding author.

Abstract

Background
Benzodiazepines are frequently prescribed during pregnancy; however, evidence about possible teratogenicity is equivocal. We aimed to evaluate the association between first-trimester benzodiazepine use and the risk of major congenital malformations.

Methods and findings
Using Korea’s nationwide healthcare database, we conducted a population-based cohort study of women who gave birth during 2011 to 2018 and their live-born infants. The exposure was defined as one or more benzodiazepine prescriptions during the first trimester. We determined the relative risks (RRs) and confidence intervals (CIs) of overall congenital malformations and 12 types of organ-specific malformations. Infants were followed from birth to death or 31 December 2019, whichever came first (up to 8 years of age). Propensity score fine stratification was employed to control for 45 potential confounders. Among a total of 3,094,227 pregnancies, 40,846 (1.3%) were exposed to benzodiazepines during the first trimester (mean [SD] age, 32.4 [4.1] years). The absolute risk of overall malformations was 65.3 per 1,000 pregnancies exposed to benzodiazepines versus 51.4 per 1,000 unexposed pregnancies. The adjusted RR was 1.09 (95% CI 1.05 to 1.13, p < 0.001) for overall malformations and 1.15 (1.10 to 1.21, p < 0.001) for heart defects. Based on mean daily lorazepam-equivalent doses, the adjusted RRs for overall malformations and heart defects were 1.05 (0.99 to 1.12, p = 0.077) and 1.12 (1.04 to 1.21, p = 0.004) for <1 mg/day and 1.26 (1.17 to 1.36, p < 0.001) and 1.31 (1.19 to 1.45, p < 0.001) for >2.5 mg/day doses, respectively, suggesting a dose–response relationship. A small but significant increase in risk for overall and heart defects was detected with several specific agents (range of adjusted RRs: 1.08 to 2.43). The findings were robust across all sensitivity analyses, and negative control analyses revealed a null association. Study limitations include possible exposure misclassification, residual confounding, and restriction to live births.

Conclusions
In this large nationwide cohort study, we found that first-trimester benzodiazepine exposure was associated with a small increased risk of overall malformations and heart defects, particularly at the higher daily dose. The absolute risks and population attributable fractions were modest. The benefits of benzodiazepines for their major indications must be considered despite the potential risks; if their use is necessary, the lowest effective dosage should be prescribed to minimize the risk.

논문정보

형식Research article
게재일2022년 03월 (BRIC 등록일 2022-03-14)
연구진국내 연구진
분야 의약학 > 약학

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